Our central hypothesis is that induction of robust, reproducible and durable, tolerance to cardiac allografts will 1) result in long-term graft sun/ival, 2) preserve normal graft function, and 3) prevent cardiac allograft vasculopathy (CAV) without long term immunosuppression. Recent studies have demonstrated that the cotrahsplantation of vascularized donor thymus induces rapid and stable tolerance to MHC disparate hearts in miniature swine. The goal of this Project is to extrapolate this innovative strategy to nonhuman primates. However, preliminary attempts to co-transplant vascularized thymus and heart allografts in nonhuman primates resulted in early loss of the donor thymus followed by rejection of the heart. To explain this screpancy, we hypothesize that nonhuman primate thymus grafts are more susceptible to early immune injury and inflammation than the porcine thymus grafts and that this early damage prevents cyiniomolgus thymus grafts from contributing fully to the induction of tolerance. We further hypothesize that the three most likely causes of early thymus injury in cynomolgus recipients are: 1) the early depletion of salutary host Tregs by high-dose ATG therapy, 2) the homeostatic expansion of deleterious memory T ceils by high-dose ATG therapy, and 3) the inflammation associated with the surgical procedure Our goal is develop an innovative and integrated strategy to block each of these events, preserve early thymic function and allow the transplanted thymus to participate fully in the induction of tolerance to cotransplanted cardiac allografts. Our aims are 1) determine whether expanding host regulatory T cells in vivo will abrogate early thymic loss, 2) determine whether depleting or inhibiting memory T cells will prevent early thymic rejection, and 3) determine if dampening the pro-inflammatory response will diminish early thymus injury and promote tolerance in heart en bloc thymus allograft recipients. RELEVANCE (See instructions): Heart transplant recipients do not survive long enough because the drugs used to prevent the immune system from attacking the organs are not completely effective and they make transplant recipients more susceptible to infections and cancer. We will find new ways to transplant organs without drugs using tolerance which makes the organs immunologically invisible to the recipient.